Method and dosage form for dispensing a bioactive substance

ABSTRACT

A method of manufacturing a bioactive fluid dose on an ingestible sheet, comprising the steps of advancing the ingestible sheet to a dispense position, and activating a fluid ejector to dispense essentially a drop of a bioactive fluid onto the ingestible sheet.

BACKGROUND

[0001] 1. Field of the Invention

[0002] The present invention relates to a method and dosage form formanufacturing pharmaceutical doses. More particularly the presentinvention relates to a method for manufacturing pharmaceutical doses onan ingestible sheet.

[0003] 2. Description of the Art

[0004] Oral administration of pharmaceuticals is one of the most widelyused methods to provide effective therapy for a variety of illnesses.Many powdered medications are typically administered orally to a personin a dosage form such as tablets or capsules, while still others are inliquid form. The release of orally administered medications falls intotwo broad categories, buccal or sublingual administration, and oraldissolution. For example, enteric coated tablets that release themedication in the intestinal tract of the patient. Further, manyindividuals suffer from chronic health problems that require the regularadministration of medicaments. Diseases such as diabetes, allergies,epilepsy, heart problems, AIDS, and even cancer requires the regulardelivery of precise doses of medicaments if patients are to survive overlong periods of time. Such chronic treatment creates the need toregularly obtain additional medication. This can be extremelytroublesome for those patients that lack the mobility to easily travelto a pharmacist to refill medications, such as the elderly and infirm.Thus, a method and a dosage form that provides the ability to makecustom doses, outside of the large pharmaceutical manufacturing plants,is desirable.

[0005] Most pharmaceuticals involve dosage units in the microgram tomilligram range of the purified active ingredient or ingredients. Thus,many pharmaceutical doses in tablet or liquid form are made informulations of a predetermined quantity of pharmaceutical units in eachdose. Such pharmaceutical doses are frequently available in fixeddifferent strengths, such as 50 mg, 100 mg, etc.

[0006] Unfortunately, such conventional oral dosage forms suffer from anumber of disadvantages. Typically, to effectively handle and dispensesmall doses a considerable amount of adjuvant material must be added inorder that the final dosage form is of a manageable size. Thus, typicalmethods for manufacturing include the mixing of the pure drug withvarious other substances commonly referred to as excipients or diluentsthat are therapeutically inert and acceptable by regulatory bodies, suchas the FDA. Excipients may also protect the drug from deterioration byoxidation, humidity, and light. Palatability can be improved through theaddition of flavorants and identification by use of colorants. Thismixing process often requires the use of sophisticated, complexexpensive machinery. Certain excipients may be needed to improve theflowability of the drug and diluents through the mixing machinery.Therefore, a method and dosage form that reduces the mixing of theactive drug with other substances, and utilizes less complex andexpensive machinery would also be desirable.

[0007] These therapeutically inactive or inert materials also have thedisadvantage that each such material must be evaluated before use interms of potential incompatibilities with the medicaments present. Forexample, some of these materials, such as lubricants or disintegrants,may present problems concerning the bioavailability of the activeingredient. Further, the certification of new drugs is a lengthy andcostly process involving animal studies followed by chemical trials toestablish both the efficacy and safety of the new drug. Because apharmaceutical's characteristics may be affected by changes inmanufacturing and/or packaging, the approval process limits the approvalto a particular manufacturing and packaging process. Thus, the abilityto rapidly and easily change dosage units is extremely limited inconventional pharmaceutical manufacturing processes.

[0008] Drugs with a narrow therapeutic range must also be preciselydosed. If the patient falls below the range, the desired effect will notoccur. However, if the patient is above the range then the risk of toxiceffects increases. Clinicians assume the dose units manufactured areuniform and that generic equivalents have equal bioavailability. Themany FDA generic formulation rejections and recalls for pharmaceuticalsthat have too high or low of a drug level, however, are evidence thataccuracy and precision are still challenges for pharmaceuticalmanufacturing.

[0009] The ability to easily make a custom dose using tablets orcapsules utilizing current technology is also difficult. It is virtuallyimpossible to split or divide a capsule to decrease the doseadministered requiring that the smallest dose be predetermined. Further,in the case of tablets a patient or pharmacist may often encounterdifficulty in splitting or dividing even relatively large tablets thathave a notch or groove at a predetermined breaking point to form a lowerdosage unit. The splitting or breaking often results in fragments ofunequal size. Thus, a method and dosage form that allows for variabledoses to be formed outside the pharmaceutical manufacturing plant isdesirable.

SUMMARY OF THE INVENTION

[0010] A method of manufacturing a bioactive fluid dose on an ingestiblesheet, comprising the steps of advancing the ingestible sheet to adispense position, and activating a fluid ejector to dispense at leastone drop of a bioactive fluid onto the ingestible sheet.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011]FIG. 1a is a perspective view of a bioactive fluid cartridgeaccording to an embodiment of this invention;

[0012]FIG. 1b is a perspective view of fluid ejection cartridges heldwithin a carriage according to an embodiment of this invention;

[0013]FIG. 1c is a perspective view of fluid ejection cartridges and animage acquisition system held within a carriage according to analternate embodiment of this invention;

[0014]FIG. 2a is a perspective view of a bioactive fluid dispensingsystem according to an embodiment of this invention;

[0015]FIG. 2b is a perspective view of a bioactive fluid dispensingsystem with an ingestible sheet tray according to an alternateembodiment of this invention;

[0016]FIG. 3 is a cross-sectional view of a fluid ejection cartridgeaccording to an alternate embodiment of this invention;

[0017]FIG. 4 a perspective view of an ingestible sheet according to anembodiment of this invention;

[0018]FIG. 5a is a plan view of an ingestible sheet according to analternate embodiment of this invention;

[0019]FIG. 5b is a cross-sectional view of the ingestible sheet shown inFIG. 5a.

[0020]FIG. 6a is a cross-sectional view of a method for generating adosage according to an embodiment of this invention;

[0021]FIG. 6b is a cross-sectional view of a method for generating adosage according to an alternate embodiment of this invention;

[0022]FIG. 6c is a cross-sectional view of a method for generating adosage according to an alternate embodiment of this invention;

[0023]FIG. 6d is a cross-sectional view of a method for generating adosage according to an alternate embodiment of this invention;

[0024]FIG. 7a is a perspective view of a process for manufacturing adosage form according to an alternate embodiment of this invention;

[0025]FIG. 7b is a perspective view of an encapsulated and unitizedsingle dose according to an embodiment of this invention;

[0026]FIG. 7c is a plan view of a process for manufacturing a dosageform according to an alternate embodiment of this invention;

[0027]FIG. 8a is a perspective view of a dosage form to vary the amountof the bioactive fluid released over time according to an embodiment ofthis invention;

[0028]FIG. 8b is a perspective view of a dosage form to vary the amountof the bioactive fluid released over time according to a first alternateembodiment of this invention;

[0029]FIG. 8c is a perspective view of a dosage form to vary the amountof the bioactive fluid released over time according to a secondalternate embodiment of this invention;

[0030]FIG. 9a is a plan view of a dosage form containing userinformation according to an embodiment of this invention;

[0031]FIG. 9b is a plan view of a dosage form containing userinformation and manufacturing information according to an alternateembodiment of this invention;

[0032]FIG. 10a is a cross-sectional view of a process for manufacturinga dosage form according to a third alternate embodiment of thisinvention;

[0033]FIG. 10b is a cross-sectional view of a dosage form manufacturedusing the process shown in FIG. 10a;

[0034]FIG. 11 is a block diagram of a bioactive fluid dispensing systemfor the interactive dispensing of a bioactive fluid on an ingestiblesheet according to an embodiment of this invention;

[0035]FIG. 12 is a flow diagram of an interactive method for generatinga dosage form according to an embodiment of this invention;

[0036]FIG. 13a is a flow diagram showing a more detailed view of thesteps for loading materials shown in FIG. 12;

[0037]FIG. 13b is a flow diagram showing a more detailed view of thesteps for reading information from materials shown in FIG. 12;

[0038]FIG. 13c is a flow diagram showing a more detailed view of thesteps for requesting information shown in FIG. 12;

[0039]FIG. 13d is a flow diagram showing a more detailed view of thesteps for specifying information shown in FIG. 12;

[0040]FIG. 13e is a flow diagram showing a more detailed view of thesteps for verifying information shown in FIG. 12;

[0041]FIG. 13f is a flow diagram showing a more detailed view of thesteps dosing the bioactive fluid on the ingestible sheet shown in FIG.12;

[0042]FIG. 13g is a flow diagram showing a more detailed view of thesteps printing information shown in FIG. 12.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] The present invention advantageously uses the multi-dropdeposition capability of a fluid ejection cartridge to dispensepharmaceuticals on an ingestible sheet. Although one embodimentdescribes the use of a thermally activated fluid ejection cartridge todispense medications in the form of drops on an ingestible media, othermethods of activation such as, piezoelectric and acoustic activation mayalso be used in the present invention. The fluid ejection cartridge ofthe present invention is a drop-on-demand type fluid dispenser. Thepresent invention provides greater control of the drug dose than atypical diluting and mixing apparatus by producing precise andrepeatable doses onto an ingestible sheet. Another feature of thepresent invention is the ability to dispense multiple differentpharmaceuticals in varied quantities onto an ingestible sheet.

[0044] For purposes of this description and the present invention, theterm “bioactive” as used with fluid, composition, substance, or agent,is a composition that affects a biological function of a vertebratedirectly or as a result of a metabolic or chemical modificationassociated with the vertebrate or its vicinal environment. An example ofa bioactive fluid is a pharmaceutical substance, such as a drug, whichis given to alter a physiological condition of the vertebrate, such as adisease. A bioactive fluid is meant to include any type of drug,medication, medicament, vitamin, nutritional supplement, or othercompound that is designed to affect a biological function of avertebrate.

[0045] Referring to FIG. 1a, an exemplary embodiment of a fluid ejectioncartridge 102 of the present invention is shown in a perspective view.In this embodiment, a fluid reservoir 128, in the body portion of thefluid ejection cartridge 102, typically contains either a bioactivefluid used to generate the pharmaceutical dose or an ingestible ink usedto generate an image or characters on an ingestible sheet or othermaterial used to make a dosage form. The fluid reservoir 128 isfluidically coupled, preferably through internal passageways, to asubstrate (not shown) that is attached to the back of a nozzle layer126. The substrate (not shown) normally contains an energy-generatingelement or fluid ejector (not shown) that generates the force necessaryfor ejecting the fluid held in the reservoir. Two widely used energygenerating elements are thermal resistors and piezoelectric elements.The former rapidly heats a component in the fluid above its boilingpoint causing vaporization of the fluid component resulting in ejectionof a drop of the fluid. While the latter utilizes a voltage pulse togenerate a compressive force on the fluid resulting in ejection of adrop of the fluid. For more information on various transducers utilizedin drop-on-demand fluid ejection cartridges see Stephen F. Pond, Ph. D.Inkjet Technology and Product Development Strategies, ch 4 (Torrey PinesResearch, 2000); and more particularly for thermal inkjet technology seeJ. Stephen Aden et al., The Third-Generation HP Thermal InkJetPrinthead, Hewlett-Packard Journal, vol. 45, no. 1, pg. 41-45, February1994.

[0046] The substrate (not shown), the nozzle layer 126, nozzles 124, anda flexible circuit 125 form what is generally referred to as an ejectorhead 122. In other embodiments the ejector head 122 includes thesubstrate (not shown), the nozzle layer 126 and the nozzles 124. Thenozzle layer 126 contains one or more nozzles 124 through which fluid,that is contained in a chamber around the fluid ejectors, is ejected byactivation of the fluid ejectors (not shown) located in close proximityto the nozzles 124. Each activation of a fluid ejector results in theejection of a precise quantity of fluid in the form of a fluid drop;thus, the number of activations of the fluid ejector controls the numberof drops ejected. For more information on drop formation see for exampleJaime H. Bohorquez et al., Laser-Comparable Inkjet Text Printing,Hewlett-Packard Journal, vol. 45, no. 1, pg. 9-17, February 1994; orWilliam A. Buskirk et al., Development of a High Resolution ThermalInkjet Printhead, Hewlett-Packard Journal, vol. 39, no. 5, pg. 55-61,October 1988.

[0047] The fluid ejection cartridge 102 described in the presentinvention can reproducibly and reliably eject drops in the range of fromabout ten femto-liters to about ten micro-liters depending on theparameters of the fluid ejection cartridge such as the size and geometryof the chamber around the fluid ejector, the size and geometry of thefluid ejector, and the size and geometry of the nozzle. Thus, thepresent invention has the ability to accurately dispense a bioactivefluid with a part per million to a part per billion accuracy. This isparticularly advantageous when dispensing expensive bioactivesubstances, such as certain hormones, antibiotics, and bioactive fluidsderived from some natural products in scarce supply. The accuracy andprecision is advantageous when dispensing concentrated substances withhigh potency. In addition, a further advantage of utilizing the fluidejection cartridge 102 of the present invention is a reduction, to lessthan one percent by weight, in the amount of excess bioactive fluid thatis dispensed to assure proper label dosage. This embodiment is alsoadvantageous for utilizing a mixture of the bioactive fluid and aningestible ink contained in the fluid reservoir 128.

[0048] The nozzle layer 126 may be formed of metal, polymer, glass, orother suitable material such as ceramic. Preferably, the nozzle layer126 is formed from a polymer such as polyimide, polyester, polyethylenenaphthalate (PEN), epoxy, or polycarbonate. In an alternate embodiment,the nozzle layer 126 is formed from a metal such as a nickel baseenclosed by a thin gold, palladium, tantalum, or rhodium layer.Preferably, the components of the ejector head 122 and the fluidreservoir are formed of materials that are inert to the bioactive fluidand/or the ingestible ink which are to be dispensed therefrom. Thus,inert materials such as glass, ceramic, stainless steel, noble metals,and polymers inert to the bioactive fluid are preferred.

[0049] The fluid is selectively expelled from the one or more of thenozzles 124 by electrical signals communicated through electricalcontacts 130 and associated conductive traces 132 disposed on theflexible circuit 125. In the preferred embodiment, the flexible circuit125 is typically bent around an edge of the fluid ejection cartridge 102and secured. The electrical traces 132 are routed from the electricalcontacts 130 to bond pads on the substrate (not shown) to provideelectrical connection for the fluid ejection cartridge 102. Thus, bycommunicating the proper electrical signal through the electricalcontacts 130 a fluid ejector is activated the appropriate number oftimes to eject a predetermined number of drops.

[0050] An information storage element 133 is disposed on cartridge 102.Preferably, the information storage element 133 is coupled to a flexiblecircuit such as the flexible circuit 125 as shown in FIG. 1a. Theinformation storage element 133 is any type of memory device suitablefor storing and outputting information that may be related to propertiesor parameters of the bioactive fluid contained within the fluidreservoir 128. Preferably, the information storage element 133 is amemory chip mounted on the flexible circuit 125 and electrically coupledthrough the electrical traces 132 to the electrical contacts 130.Alternatively, the information storage element 133 can be encapsulatedin its own package with corresponding separate electrical traces andcontacts.

[0051] When the fluid ejection cartridge 102 is either inserted into, orutilized in, a dispensing system the information storage element 133 iselectrically coupled to a controller that communicates with theinformation storage element 133 to use the information or parametersstored therein. However, other forms of information storage can also beutilized for the information storage element 133, such as a bar code orother device that allows storage of information. Further, theinformation storage element 133 can be mounted elsewhere on or withinthe body of the fluid ejection cartridge 102 with appropriate contactsand electrical connections to access the storage element depending onthe particular application. In addition, the information storage element133 can also be placed on an off-axis container utilized withsemi-permanent ejector heads or cartridges.

[0052] The information storage element 133 may contain information suchas the particular bioactive fluid or other material contained in thefluid reservoir 128; the quantity of material remaining in the fluidreservoir 128 based on the number of drops dispensed or the number oftimes the fluid ejector has been activated. Other information caninclude the date of manufacture, inspection dates, quality controlinformation, dispensing system parameters, and customer/patientinformation.

[0053] The fluid ejection cartridge 102, or more preferably a set ofindividual fluid ejection cartridges 102 and 103, capable of ejectingdrops of bioactive fluid or ingestible ink or a combination thereof fromejector heads 122 and 123 are held within a carriage 111, as illustratedin a perspective view in FIG. 1b. Alternative embodiments can includeone or more semi-permanent ejector heads that are replenished from oneor more fluidically-coupled off-axis fluid containers, or a single fluidejection cartridge having one or more fluids available within the fluidejection cartridge and fluid ejecting nozzles designated for each fluidintegrally coupled with each fluid reservoir, or a single fluid ejectioncartridge having a mixture of the bioactive fluid and ingestible ink.The present invention can be satisfactorily employed by at least thesealternatives.

[0054] An alternate embodiment of the present invention where a carriage111′ contains an image acquisition system 150 is shown in FIG. 1c. Inthis embodiment, the image acquisition system 150 contains a camera 151and a light source 152. As the cartridge 102 ejects drops of a bioactivefluid onto the ingestible sheet, the drops may exhibit spots on thesheet having various visual or otherwise detectable geometric aspects,such as area extent, shape, and position. Preferably, the light source152 is positioned relative to the camera 151 so that the camera 151 canimage these detectable geometric aspects. Although as depicted in FIG.1c the light source 152 comprises a single source, multiple sources canalso be used. The light source 152 is preferably a light emitting diode(LED), although other light sources such as light bulbs or lasers canalso be utilized.

[0055] The image acquisition system 150 also contains, a camera andlight source, controller 153 that is preferably coupled to a drop-firingcontroller 214 as shown in FIG. 2a. When either fluid ejection cartridge102 or 103 is activated by the drop-firing controller 214, to dispensebioactive fluid or ingestible ink on an ingestible sheet, the cameracontroller 153 is correspondingly triggered by the drop-firingcontroller 214; thus activating the camera 151 to gather imageinformation pertaining to a portion of the surface of an ingestiblesheet on which either a bioactive fluid or ingestible ink has beendeposited. The camera 151 as shown in FIG. 1c can be any camera that canimage the desired qualities on an ingestible sheet such as a camera thatcaptures 2 dimensional images or line scan cameras that capture anarrow-stripped portion of the surface being imaged and thesenarrow-stripped portions are combined to for a complete two dimensionalimage.

[0056] In addition to capturing images of either the bioactive fluid oringestible ink or other material dispensed on the ingestible sheet theimage acquisition system 150 can also be utilized to capture images ofinformation that has been placed on an ingestible sheet prior todeposition of the bioactive fluid or ingestible ink. Examples of suchinformation are the composition of the ingestible sheet or results ofquality control testing; data on compatibility with the bioactivefluids, i.e. whether the ingestible sheet is compatible or incompatiblewith bioactive fluid being dispensed; patient information such asheight, weight, name, age, prescribed dose etc.; expiration dates,temperature and/or humidity sensors, indicating that the ingestiblesheet is no longer effective or it has been exposed to an extreme whichcould hinder its effectiveness. Although the image acquisition system150, as depicted in FIG. 1c, is mounted in carriage 111′, otherarrangements can also be utilized such as mounting the image acquisitionsystem 150 on a separate carriage, or locating the image acquisitionsystem in a different portion of a bioactive fluid dispensing system 200shown in FIG. 2a.

[0057] The essential parts of a bioactive fluid dispensing system 200according to an embodiment of the present invention is shown in a blockdiagram in FIG. 2a. In this embodiment, a platen to which an ingestiblesheet 204, such as a starch or glycerin based paper, is transported bymechanisms that are known in the art. The carriage 111 is typicallysupported by a slide bar 213 or similar mechanism within the system 200and physically propelled along the slide bar 213 to allow the carriage111 to be translationally reciprocated or scanned back and forth acrossthe ingestible sheet 204. The scan axis, X, is indicated by an arrow inFIG. 2a.

[0058] Under control of the drop firing controller 214 and a positioncontroller 218, the carriage 111 scans across the ingestible sheet 204,and fluid drops are selectively ejected from fluid ejectors disposedwithin the fluid ejection heads of the set of fluid ejection cartridges102 and 103 onto the ingestible sheet 204. The power to activate thefluid ejectors is supplied by a power supply 215. The drops are ejectedto form predetermined dot matrix patterns, forming both thepharmaceutical dose from the cartridge containing the bioactive fluid,and images or alphanumeric characters from the cartridge containing theingestible ink.

[0059] Rasterization of the data can occur in a host computer such as apersonal computer or PC (not shown) prior to the rasterized data beingsent, along with the system control commands, to the system, althoughother system configurations or system architectures for therasterization of data are possible. This operation is under control ofsystem driver software resident in the system's computer. The systeminterprets the commands and rasterized data to determine which dropejectors to fire. An arrow in FIG. 2a indicates the fluid droptrajectory axis, Z, directed from the fluid ejection cartridges 102 and103 toward the ingestible sheet 204. When a swath of fluid ejection hasbeen completed, the ingestible sheet 204 is moved an appropriatedistance along the ingestible sheet axis, Y, indicated by the arrow, inpreparation for the next swath. This invention is also applicable tobioactive fluid dispensing systems employing alternative means ofimparting relative motion between the fluid ejection cartridges and theingestible sheet, such as those that have fixed fluid ejectioncartridges and move the ingestible sheet in one or more directions, andthose that have fixed ingestible sheet and move the fluid ejectioncartridges in one or more directions.

[0060] As can be appreciated from a preferred embodiment shown in FIG.2a, the ingestible sheet 204 is advanced into a fluid ejection areabeneath the ejector heads 122 and 123 (shown in FIG. 1b) by a sheetpositioning mechanism commonly referred to as a sheet positioner orsheet advancer including rollers 217, a platen motor 216, and tractiondevices (not shown). In a preferred embodiment, the fluid ejectioncartridges 102 and 103 are incrementally drawn across the ingestiblesheet 204 on the platen by a carriage motor 212 in the ±X direction,perpendicular to the Y direction of entry of the medium. The platenmotor 216 and the carriage motor 212 are typically under the control ofthe sheet and cartridge position controller 218. An example of such apositioning and control apparatus may be found described in U.S. Pat.No. 5,070,410. Thus, the ingestible sheet 204 is positioned in alocation so that the fluid ejection cartridges 102 and 103 may ejectdrops of fluid onto the ingestible sheet 104 as required for theparticular dose being generated, and the particular data being writtenthat is input to the drop-firing controller 214 of the bioactive fluiddispensing system 200. These drops of fluid are expelled from selectedorifices in the ejector heads 122, 123 (as shown in FIG. 1b) in a bandparallel to the scan direction as the fluid ejection cartridges 102 and103 are translated across the ingestible sheet 204 by the carriage motor212. Once the fluid ejection cartridges 102 and 103 have reached the endof their traverse in the X direction on the slide bar, they are eitherreturned back along the support mechanism while continuing to ejectfluid or returned without fluid ejection.

[0061] When the fluid ejection cartridges 102, 103 reach the end oftheir travel at an end of a fluid ejection swath on the ingestible sheet204, the ingestible sheet 204 is conventionally incrementally advancedby the position controller 218 and the platen motor 216. Once the fluidejection cartridges have reached the end of their traverse in the Xdirection on the slide bar 213 or similar support mechanism, they areeither returned back along the slide bar 213 while continuing to ejectfluid or returned without ejecting. The ingestible sheet 204 may beadvanced by an incremental amount equivalent to the width of thefluid-ejecting portion of the fluid-ejecting head or some fractionthereof related to the spacing between the nozzles. Control of theingestible sheet 204, positioning of the fluid ejection cartridge, andselection of the correct fluid ejectors for creation of both thebioactive fluid dose and the image or character written is determined bythe position controller 218 and the drop-firing controller 214. Thecontrollers may be implemented in a conventional electronic hardwareconfiguration and provided operating instructions from conventionalmemory 219.

[0062] The bioactive fluid dispensing system 200 also contains a heater221 coupled to a heater controller 220 as shown in FIG. 2a. The heater221 heats the ingestible sheet 204 to remove water and other solventsdeposited on the ingestible sheet 204 after deposition of the bioactivefluid or ingestible ink. The heater also contains a temperature sensor(not shown) that is coupled to the heater controller 220 to maintain theingestible sheet 204 at the appropriate temperature. The particulartemperature that the temperature sensor maintains depends on theparticular bioactive fluid or ingestible ink being dispensed, and on theparticular ingestible sheet 204 being utilized. Although the heater 221is located above the rollers 217 as depicted in FIG. 2a the heater canalso be located in other portions of the bioactive fluid dispensingsystem 200 such as underneath the ingestible sheet 204 in front of therollers 217.

[0063] A perspective view of an alternate embodiment of the presentinvention where the bioactive fluid dispensing system 200 includes aningestible sheet tray 299 is shown in FIG. 2b. In this embodiment, thetray 299 holds separate ingestible sheets 204′ that are advanced intothe fluid ejection area beneath ejector heads (not shown) by rollers217′ and other mechanisms as described above in FIG. 2a. Preferably thetray 299 holds from 1 to about 250 sheets, however, depending on theparticular system, ingestible sheet, and bioactive fluid being utilized,the tray 299 may hold more than 250 sheets.

[0064] The apparatus described above makes unique use of an automatedfluid ejecting device, having at least one bioactive fluid supply in areservoir or chamber and at least one, and preferably, a plurality offluid ejectors in an array, each ejector dispensing a precise volume offluid in essentially individual droplets on each activation of the fluidejector. This arrangement enables the quantity of the bioactive fluiddispensed to be varied in a specified area of the ingestible sheetthereby enabling either custom, or a wide range of doses to be moreeasily prepared. The apparatus or system as depicted in FIGS. 2a and 2 bmay be used in a manufacturing environment, a pharmacy, or even in otherdispensing locations such as in a hospital, home etc. to automaticallyprepare pharmaceutical doses in response to patients needs.

[0065] A cross-sectional view of an alternate embodiment of the presentinvention where a fluid ejection cartridge 302 includes three fluidreservoirs 327, 328, and 329 contained within a cartridge body 334 isshown in FIG. 3. In this embodiment, a substrate 336 is attached to theouter surface of the cartridge body 334, and includes three groups offluid ejectors 346, 346′ and 346″, in fluid communication with the threefluid reservoirs 327, 328, and 329 via three fluid routing channels 337,338, and 339 respectively. Three fluid filters 340, 341, and 342, aremounted within the fluid reservoirs 327, 328, and 329, respectively.These filters are preferably constructed from stainless steel wire meshof a desired porosity to provide good filtration of solid particles andair bubbles when fluid passes from the three fluid reservoirs 327, 328,and 329 into the three fluid routing channels 337, 338, and 339.

[0066] Attached to the substrate 336 is a firing chamber layer 344 thatdefines the volume around each fluid ejector. Attached to the firingchamber layer 344 is a nozzle layer 326 that contains three groups ofnozzles 324, 324′ and 324″. The fluid will flow from the three fluidreservoirs 327, 328, and 329 through the three fluid filters 340, 341,and 342 into the three fluid output ports 337, 338, and 339 through thesubstrate 336. A firing chamber layer 344 includes fluid channels (notshown) and a firing chamber (not shown) formed into the layer that feedsfluid to the ejectors 346, 346′ and 346″. Upon appropriate activation,the ejectors 346, 346′ and 346″ initiate the ejection of fluid out ofthe fluid ejection cartridge 302 through the three groups of nozzles324, 324′ and 324″. Preferably, each group of nozzles is in a column andmore preferably in staggered columns, however other patterns, such ascircular patterns can also be utilized. This embodiment is particularlyadvantageous when the user desires a self-contained cartridge orintegral replaceable unit containing the bioactive fluid, the ingestibleink, and a protective coating that is dispensed over the dispensedbioactive fluid. This embodiment is also advantageous when the user hasthree compatible bioactive fluids that can be dispensed on the samesheet.

[0067] Although the properties of the ingestible sheets used inaccordance with the present invention depend both on the particularbioactive fluid being dispensed and on the particular materials utilizedin the sheet, it is generally preferable that the sheets are safelyedible or ingestible, and do not have an objectionable “feel” in themouth. In addition, the sheets preferably dissolve or degrade in bodyfluids and/or enzymes. However, the sheets can be made of non-degradablematerials that are readily eliminated by the body. Preferably the sheetsare hydrophilic and readily disintegrate in water and more preferablythe dissolution or disintegration of the sheets is enhanced at the pH ofthe fluids in the stomach or upper intestine. Further, ingestible sheetsthat minimize unintended interactions with the bioactive fluid dispensedon the sheets and sheets that minimize the release of any sheetcomponent that would cause unintended interactions with the bioactivefluid upon dissolution of the sheet, are also desirable.

[0068] Additional properties of the ingestible sheet that are desirableare the ability to remain stable over extended periods of time, atelevated temperatures, and at high or low levels of relative humidity.In addition, it is also preferable that the ingestible sheets aregenerally a poor medium for the growth of microorganisms to reducespoilage. Further, ingestible sheets that possess reasonable mechanicalproperties such as tensile strength and tear strength are desirable toallow the sheets to be processed through the various steps offabrication of the final dosage form using methods such as arerecognized in the art.

[0069] Ingestible sheets that can be utilized in the present inventioncan be one or a mixture of organic film formers generally classifiedinto two broad categories, i.e. polymeric and paper. Examples of suchfilm formers are starch (i.e. both natural and chemically modified) andglycerin based sheets with or without a releasable backing. Otherexamples include, proteins such as gelatin, cellulose derivatives suchas hydroxypropylmethylcellulose and the like; other polysaccharides suchas pectin, xanthan gum, guar gum, algin and the like; synthetic polymerssuch as polyvinyl alcohol, polyvinylpyrrolidone and the like. Examplesof ingestible sheets or edible films that can be utilized are those thatare based on milk proteins, rice paper, potato wafer sheets, and filmsmade from restructured fruits and vegetables.

[0070] In particular, sheets or films made from restructured fruits andvegetables are advantageous were it is desirable to mask or modify thetaste or smell of the bioactive fluid being delivered. Further, theserestructured fruit and vegetable films also provide a convenientapproach to encourage children to take various medications as well asproviding a more pleasing and varied taste for various medications takenby adults. For more information on restructured fruit and vegetablefilms, see for example U.S. Pat. Nos. 5,543,164 and 6,027,758.

[0071] Dispensing the bioactive fluid on an ingestible sheet containinga water-expandable foam is preferable for those applications desiringrapid release of the bioactive fluid once ingested. Examples of suchmaterials are an oxidized regenerated cellulose commercially availablefrom Johnson and Johnson under the trademark SURGICEL®, and a porcinederived gelatin powder commercially available from Pharmacia Corporationunder the trademark GELFOAM®.

[0072] The form of the ingestible sheet that can be utilized in thepresent invention can be any of the forms generally recognized in theart such as those used for paper, cardboard or polymeric films. Theingestible sheet or roll preferably is uniform in thickness and inwidth. Although the thickness of the ingestible sheet will depend on theparticular bioactive fluid being dispensed, the particular ingestiblesheet being utilized, and the particular method of manufacture used; thethickness of the ingestible sheet preferably ranges from about 10 toabout 350 microns and more preferably from about 25 to about 100 micronsthick.

[0073] The dosage forms produced in accordance with the presentinvention are eminently suited to span the range of production fromindividualized doses made in a home or hospital environment to the highspeed high volume production in a pharmaceutical manufacturingenvironment. Thus, the particular width and length will not only dependon both the particular bioactive fluid being dispensed and theparticular ingestible sheet being utilized, but more particularly on theparticular method of manufacture used. Thus, the ingestible sheet can bein roll or individual sheet forms with widths varying from approximatelyone centimeter to several meters, and lengths from a few centimeters toseveral thousand meters, although other lengths and widths can also beutilized.

[0074] An embodiment of an ingestible sheet that is preferable for bothhigh speed high volume manufacturing as well as for custom,individualized dispensing is illustrated in a perspective view in FIG.4. In this embodiment, an ingestible sheet 404 is in the form of a rollthat contains perforations 447 that delineates each dosage form 405 and405′. In this embodiment, a bioactive fluid is dispensed preferably in atwo-dimensional array, although other patterns can also be utilized,onto a first portion of the ingestible sheet 404. A sheet advancer (notshown) then advances the ingestible sheet 404 and a second twodimensional array or alternate pattern is dispensed on a second portionof the ingestible sheet. The first and second portions form dosage forms405 and 405′ respectively.

[0075] Preferably, after the bioactive fluid is dispensed on the dosageform 405 the user or system separates the dosage form 405 from thedosage form 405′ by tearing, by cutting along the perforations 447, orby punching out the dispensed areas of the sheet. The user or system canalso separate the dosage form 405 from the dosage form 405′ beforedispensing of the bioactive fluid. This embodiment is particularlyadvantageous for systems such as those that have fixed fluid ejectioncartridges; however, it can also be utilized in other systems as well.Preferably, the ejector head is approximately the width of theingestible sheet 404 and the platen (not shown) moves the ingestiblesheet in the direction of arrow 448 allowing both the dispensed dose ofbioactive fluid as well as the appropriate characters or symbolsutilizing the ingestible ink to be formed.

[0076] An alternate embodiment of an ingestible sheet that can also beused for custom, individualized pharmaceutical doses is shown in a planview in FIG. 5a and in a cross-sectional view in FIG. 5b. In thisembodiment, an ingestible sheet 504 is in the form of a sheet with aplurality of dosage forms 505 where each dosage form 505 contains dosageform separators 547 around its peripheral edge. Preferably, after thebioactive fluid is dispensed on the plurality of the dosage forms 505contained in the ingestible sheet 504 the user or system separates thedosage form 505 from the dosage forms 505′ and 505″ by bending or, bypushing up in the center of the dosage form 505, or some otherconvenient method and peeling the dosage form 505 from a releasablebacking 549 shown in FIG. 5b. This embodiment is particularlyadvantageous for systems used to dispense custom pharmaceutical doses athome, in a hospital or a pharmacy; however, it can also be utilized inother systems as well. Although FIG. 5a shows the ingestible sheet 504utilizing dosage form separators 547, the ingestible sheet 504 canutilize any convenient means of separation such as perforations shown inFIG. 4.

[0077] An embodiment of a method for generating a dosage form where thebioactive fluid is dispensed onto the ingestible sheet is shown in across-sectional view in FIG. 6a. In this embodiment, a drop-firingcontroller in a fluid dispensing system (not shown) activates one and,typically, a plurality of fluid ejectors, of a fluid ejection cartridge(not shown), to eject fluid drops 650, 650′, and 650″ of the bioactivefluid onto an ingestible sheet 604 forming deposits 651, 651′, and 651″,respectively. For clarity in understanding the invention, the fluiddrops 650, 650′, and 650″ are shown as being deposited on the surface ofthe ingestible sheet 604. Although this will occur for non-porous,non-absorbing ingestible sheets, typically, the ingestible sheet 604will be a porous and absorbing material which will allow the bioactivefluid to be absorbed into the interior of the ingestible sheet 604. Adosage form 605 is generated when the required number of fluid drops ofthe bioactive fluid, to create the desired pharmaceutical dose, havebeen dispensed on a portion of the ingestible sheet 604. Preferably, thedosage form 605 contains a two-dimensional array of the deposits 651,651′ and 651″ of the bioactive fluid on the ingestible sheet 604.However, other arrangements can also be utilized, such as overlappingdeposits forming a layer, or a different geometrical arrangement of thedeposits 651, 651′, and 651″.

[0078] An alternate embodiment of the present invention where theprocess used for generating a dosage form includes a barrier materialdeposited over the bioactive fluid is shown in a cross-sectional view inFIG. 6b. In this embodiment, the drop-firing controller activates oneand, typically, a plurality of fluid or barrier ejectors, to eject fluiddrops of a barrier material over the deposits 651, 651′, and 651″ of thebioactive fluid to form barrier deposits 652, 652″, and 652″. Thebarrier deposits 652, 652′, and 652″ and deposits 651, 651′, and 651″ ofthe bioactive fluid on the ingestible sheet 604 form dosage form 606.The barrier material acts to seal the bioactive fluid from theenvironment. Depending on the particular bioactive fluid dispensed, andthe particular ingestible sheet used, the barrier material providesvarious protective properties, such as humidity protection, protectionfrom oxidation, inactivation, or contamination. The barrier material isan edible coating made from a suitable polymeric material such as awater-soluble polyoxyethylene or cellulose ether derivative. Inaddition, preferably the barrier material is an inert material, whichwill not interact with the deposited bioactive fluid. Further, thebarrier material may also act as an adhesive as will be discussed later.In this embodiment, the fluid ejectors activated by the drop-firingcontroller are either, a different subgroup of fluid ejectors on thefluid ejection cartridge used to dispense the bioactive fluid, or adifferent fluid ejection cartridge.

[0079] An alternate embodiment of the present invention where theprocess used for generating a dosage form includes ingestible inkdeposited over the bioactive fluid is shown in a cross-sectional view inFIG. 6c. In this embodiment, after the bioactive fluid and the barriermaterial has been deposited onto the surface of the ingestible sheet604, as described above, the drop-firing controller activates one and,typically, a plurality of ink ejectors, to eject fluid drops of aningestible ink at various locations on the ingestible sheet 604 to formdots 654, 654′ and 654″. The dots 654, 654′ and 654″ are deposited inpatterns using dot matrix manipulation or other means to generate animage, alphanumeric characters, or a machine understood code such as aone or two dimensional bar code, on the ingestible sheet 604. The dots654, 654′ and 654″, the barrier deposits 652, 652″, and 652″ anddeposits 651, 651′, and 651″ of the bioactive fluid on the ingestiblesheet 604 form dosage form 607.

[0080] An alternate embodiment of the present invention where theprocess used for generating a dosage form includes deposition of morethan one bioactive fluid onto the ingestible sheet 604′ is shown in across-sectional view in FIG. 6d. In this embodiment, the deposits 651,651′, and 651″ of the bioactive fluid and the deposits 652, 652′ and652″ of the barrier material have been formed on the ingestible sheet604′ as described above. Next, the drop-firing controller activates oneand, typically, a plurality of fluid ejectors, to eject fluid drops of asecond bioactive fluid on the ingestible sheet 604′ to form deposits656, 656′ and 656″. In this embodiment, the fluid ejectors activated bythe drop-firing controller to eject the second bioactive fluid areeither, a different subgroup of fluid ejectors on the fluid ejectioncartridge used to dispense the first bioactive fluid, or a differentfluid ejection cartridge.

[0081] After the second bioactive fluid has been dispensed, a secondbarrier is then formed over the deposits 656, 656′ and 656″ formingbarrier deposits 658, 658′ and 658″ forming dosage form 608. Preferablythe second barrier material is the same as the first, however, dependingon the properties and compatibilities of the first and second bioactivefluids as well as the first barrier material the second barrier materialmay be different from the first barrier material. Although FIG. 6ddepicts two different bioactive fluids deposited on the ingestiblesheet, more than two bioactive fluids can be deposited on an ingestiblesheet.

[0082]FIGS. 6a-6 d depict isolated deposits of the bioactive fluid andbarrier material being deposited onto the ingestible sheet; however, bydepositing overlapping deposits of, either or both, the bioactive fluidand barrier material layers of each material can be formed. In addition,the order of deposition can also be varied depending on the particularapplication. For example, the ingestible ink can be deposited before thebioactive fluid and the barrier material. Further, the ingestible sheet604 or 604′ shown in FIGS. 6a-6 d can have, either or both, a releasablebacking (not shown) or barrier material (not shown) coated on thesurface opposite to the surface on which the bioactive fluid isdispensed.

[0083] An alternate embodiment of the present invention of a process formanufacturing a dosage form containing more than one bioactive fluid isshown in a perspective view in FIG. 7a. In this embodiment, multipleingestible sheets 704, 706, and 707 each having multiple portions 760,761, 762 respectively that have a bioactive fluid deposited thereon. Thecenter ingestible sheet 704 is then sandwiched between the outer sheets706 and 707 to form a laminated structure 764 where each of the multipleportions 760, 761, 762 are positioned where the portion 761 is above theportion 760 which is above the portion 762. This arrangement forms adosage form 705 that contains multiple bioactive fluids.

[0084] Although FIG. 7a depicts three layers of ingestible sheet beinglaminated, laminated structures containing two or more layers can beutilized. The ingestible sheets 704, 706, and 707 can be formed from thesame or different materials. In addition, the various processes andresultant structures depicted in FIGS. 6a-6 b can also be utilized.Further, other films such as a barrier film or ingestible adhesive filmcan also be laminated or coated on the different ingestible sheets 704,706, and 707 to improve various properties such as water vaportransmission rate or adhesion depending on the particular bioactivefluids and the particular ingestible sheets being utilized. Subsequentto the lamination process the laminated structure 764 can further beencapsulated and unitized to form single dose 766 as shown inperspective view in FIG. 7b.

[0085] An alternate embodiment of the present invention of a process formanufacturing a dosage form containing more than one bioactive fluid isshown in a plan view in FIG. 7c. In this embodiment, an ingestible sheet704′ contains multiple portions 760′, 761′, 762′, and 763 eachcontaining a different bioactive fluid deposited thereon. The fourmultiple portions form a dosage form 705′ that contains multiplebioactive fluids. Although FIG. 7c depicts four multiple portions, theingestible sheet 704′ containing two or more multiple portions can beutilized. The various processes and resultant structures depicted inFIGS. 6a-6 b can also be utilized in this embodiment. In addition, otherfilms such as a barrier film or ingestible adhesive film can also belaminated or coated on the ingestible sheet 704′ to improve variousproperties such as water vapor transmission rate, acid resistance, ordrug release rate depending on the particular bioactive fluids and theparticular ingestible sheet being utilized. Further the multipleportions 760′, 761′, 762′ and 763 can also be utilized in the laminatedstructure 764 shown in FIG. 7a by either making a larger dosage form orby folding.

[0086] As noted above an expandable foam may be desirable for the rapidrelease of a bioactive fluid once ingested, however, some applicationsmay want to vary the amount of the bioactive fluid released over time.An advantage of the present invention is the ability to make dosageforms that can vary the amount of bioactive fluid or drug released overtime as shown in FIG. 8a-8 c. In an alternate embodiment, shown in FIG.8a, a fluid ejection cartridge (not shown) containing at least abioactive fluid ejects the bioactive fluid onto an ingestible sheet 804to form deposits 808 of the bioactive fluid dispensed in a twodimensional array over the surface of the ingestible sheet 804. In thisembodiment, a dosage form 805 contains a first edge 806 having a greaterdensity of the deposits 808 than a second edge 807 where the density ofthe deposits 808 between the first edge 806 and second edge 807 varies,forming a gradient of the bioactive fluid dispensed on the ingestiblesheet. Although as shown in FIG. 8a the bioactive fluid is dispensed inthe form of deposits 808 over the entire surface of dosage form 805other forms can also be utilized such as centering the two dimensionalarray of deposits 808 in a narrower strip in the center of the dosageform 805 running from the edge 806 to the edge 807. The dosage form 805is wound into a coil, where the edge 806 having the higher dot densityforms the edge contained in the center of the coil and the edge 807having the lower dot density forms the outer edge of the coil.

[0087] As the ingestible sheet 804 dissolves the radius of the coileddosage form 805 decreases, resulting in a smaller surface area, thus theamount of bioactive fluid released can be varied or maintained constant.For example as shown in FIG. 8a a gradient that increases as the surfacearea decreases can be used to maintain a constant or increasing releaserate depending on the particular gradient used. Thus, in this examplethe bioactive fluid is deposited in a gradient adapted to provide adosage form that, after being ingested, the amount of the bioactivefluid released increases over time. Further, the bioactive fluid canalso be deposited in a gradient adapted to provide a dosage form that,after being ingested, the amount of the bioactive fluid released remainsconstant over time However, as shown in FIG. 8b, a dosage form 805′ thatis coiled in the opposite direction where the edge 807, having the lowerdot density, forms the center of the coil and the edge 806, having thehigher dot density, forms the exterior surface of the coil; generates agradient that decreases as the surface area decreases. Such a dosageform can be used to decrease the release rate as a function of timecreating a loading dose. Thus, in this example the bioactive fluid isdeposited in a gradient adapted to provide a dosage form that, afterbeing ingested, the amount of the bioactive fluid released decreasesover time.

[0088] A perspective view of an alternate embodiment of the presentinvention where repeat dosages are formed is shown in FIG. 8c. In thisembodiment a fluid ejection cartridge (not shown) containing at leastone bioactive fluid ejects the bioactive fluid onto the ingestible sheet804 to form the deposits 808 of the bioactive fluid dispensed in a twodimensional array over discrete portions 809 on the surface of theingestible sheet 804. The dosage form 805″ is wound into a coil whereeach of the discrete portions 809 will release the deposited bioactivefluid at different times depending on the thickness of the ingestiblesheet 804, the rate of dissolution of the ingestible sheet 804 and theparticular placement of each discrete portion 809 among other variables.This embodiment provides a dosage form where a discrete amount of thebioactive substance is released at either repeatable times or discreteamounts of the bioactive substance is released at different times.Although each of the alternative embodiments shown in FIGS. 8a-8 c aredescribed in terms of fixed dot size and varying the dot density, othermethods can also be utilized such as varying the drop size and keepingthe dot density constant. This ability to vary the dosage release rateover time is an advantage over a conventionally formed tablet, whichwould release less bioactive material as the diameter of the tabledecreases. Thus, the present invention provides a dosage form where theamount of bioactive substance released over time, increases, decreases,remains constant, is repeatable, or a discrete dose is released atdifferent times.

[0089] Referring to FIGS. 9a-9 b, an alternate embodiment of the presentinvention is shown where the dosage form 905 contains user information970 to be conveyed to the user or patient. For example, FIG. 9a depictsthe user information 970 as a clock showing the time the dose is to betaken or administered. In this particular example the user information970 is deposited over the two dimensional array of the deposits 908 ofthe bioactive fluid. However, depending on the particular bioactivefluid and the particular ingestible sheet being utilized the bioactivefluid can also be deposited over the user information. Another exampleis shown in FIG. 9b where the information is a message indicating thename, date, and time to take the medicament. However, the userinformation 970 can be any symbol, icon, image, or text or combinationsthereof, such as a company logo or cartoon character. Other examples ofthe type of information that can be conveyed to the user are the name ofthe medicament, the expiration date, the flavor of the ingestible sheet,or information having some marketing value. In addition, the dosage form905 can also contain manufacturing information 972 to be used by themanufacturer and/or distributor. For example, FIG. 9b depicts themanufacturing information 972 as a two-dimensional bar code. Themanufacturing information 972, however, can be any symbol, icon, image,or text or combinations thereof. Examples of various forms are aone-dimensional bar code, a text message, a code, or hologram. Examplesof the various types of information that can be utilized in themanufacturing information 972 would be the composition of the ingestiblesheet or results of quality control testing, data on compatibility withbioactive fluids, expiration dates, or part tracking information.

[0090] A cross-sectional view of an alternate embodiment of the presentinvention where a dosage form 1005 is encapsulated in a tablet 1079 isshown in FIG. 10b. In this embodiment, a lower die chamber 1074 and anupper die chamber 1076 are substantially filled with an excipient powder1078 as shown in FIG. 10a. Dosage form 1005, which contains thebioactive fluid deposited on an ingestible sheet 1004, is positionedbetween the two die chambers such that the excipient powder formulationencases or encloses the dosage form 1005. Compressing the lower diechamber 1074 against the upper die chamber 1076 forms the tablet 1079.Preferably, the tablet is cylindrical with convex outer surfacestypically about 5 to 15 mm. in diameter and about 5 mm. in thickness.However, a variety of regular and irregular shapes and sizes can beutilized, such as elliptoids, cuboids, indentations, polygonoids andother convex and concave surfaces. Optional subsequent processesincluding dedusting, drying, and coating may be performed.

[0091] Depending on the desired pharmacokinetic characteristics of thebioactive fluid dispensed on the ingestible sheet 1004, the excipientformulation may be similar to the ingestible sheet 1004 or one mayselect is excipients that are dissimilar to the ingestible sheet toobtain tabletting or pharmacokinetic characteristics unlike theingestible sheet 1004. For example microcrystalline sugar (97% sucroseand 3% maltodextrin) or cellulose, calcium phosphate, and sodiumcarboxymethylcellulose can be used with a cellulosic-based ingestiblesheet. Sugars and corn, wheat, or rice starches can be used withstarch-based ingestible sheets. Whereas silica added to improveflowability, stearates for lubrication, and guar gum or gelatin asbinders are examples of dissimilar materials.

[0092] A preferable excipient formulation for direct compressiontabletting of a dosage form made from an ingestible sheet which does notinclude the weight of the ingestible sheet nor the weight of thebioactive fluid dispensed is: about 70 weight percent lactose, about 25weight percent microcrystalline cellulose, about 2 weight percentdi-calcium phosphate dihydrate, 2 weight percent sodiumcarboxymethylcellulose, about 0.3 weight percent fumed silica and about0.5 weight percent magnesium stearate. However, excipient ranges informulations for direct compression tabletting of a dosage form madefrom an ingestible sheet which does not include the weight of theingestible sheet nor the weight of the bioactive fluid dispensed are 0to about 80 weight percent sugar, 0 to about 25 weight percentmicrocyrstalline cellulose, 0 to about 90 weight percent calciumphosphate, about 5 to about 25 weight percent starch, about 1 to about 2weight percent sodium carboxymethylcellulose, about 0.2 to about 0.3weight percent silica and about 0.5 to about 1 weight percent magnesiumstearate can also be utilized.

[0093] In addition to improve adhesion between the excipient powderformulation and the ingestible sheet the excipient formulation can bemodified by adding natural or synthetic polymers such as proteins,carboxymethylcellulose, polyvinylacetate, gelatins, or dextrins can beutilized to improve the adhesive properties of the excipient powder. Itis also contemplated that an ingestible adhesive can be dispensedbetween the two die chambers prior to applying pressure to form thetablet. For example, a monomeric methyl or ethylcyanoacrylate typeadhesive can be utilized. Alternatively, the ingestible sheet 1004 ofthe dosage form 1005 can be perforated to allow greater contact areabetween excipient powder 1078 contained in the upper die chamber 1076and the lower die chamber 1074 or the dosage form 1005 can be formed inthe shape of a ring containing an area in the center of the dosage form1005 that allows the excipient powder in the two chambers to bond.

[0094] The process described above for compression tabletting of aningestible sheet containing a bioactive fluid is advantageous overconventional tabletting in that the number of mixing steps can bereduced as well as the need to assure thorough mixing of the excipientwith the pharmaceutical material to ensure proper dilution. In addition,flowability and drying criteria of the excipient formulation can also berelaxed.

[0095] An exemplary system 1100 for the interactive dispensing of abioactive fluid on an ingestible sheet is shown as a schematic diagramin FIG. 11. In this embodiment a processor 1180 is coupled to adrop-firing controller via dispense interface 1182. The processor 1180converts a specified quantity of the bioactive fluid to be dispensedinto a number of drops or ejections to be activated by the drop-firingcontroller. This number is transmitted via the dispense interface 1182to the drop-firing controller of the bioactive fluid dispensing system200. The specified quantity of the bioactive fluid is then ejected ontothe ingestible sheet forming a dosage form. The system 1100 alsoincludes a storage device 1186 and a display device 1184 coupled to theprocessor 1180 to store and display information. For example user inputinformation, system parameters, information and parameters associatedthe ingestible sheet can all be stored on storage device 1186 and/ordisplayed on display device 1184.

[0096] The system 1100 having the processor 1180, display device 1184,and storage device 1186 is advantageous over current methods of formingpharmaceutical doses in that it allows a user such as a doctor orpharmacist to generate variable doses as well as custom doses in theconvenience of a hospital, pharmacy, or home environment. Further, sucha system can also be utilized as a point of sale machine, in suchlocations as a pharmacy or a supermarket, to allow customers to createvariable or custom doses of vitamins, nutritional supplements, or otherover-the-counter medications.

[0097] In addition, the system 1100 also includes a user interface 1188or signal receiver that is coupled to the processor 1180 and is alsocoupled via communication channel 1193 to an external communicationnetwork 1190 as shown in FIG. 11. Preferably, the external communication1190 is a digital network such as what is commonly referred to as theInternet. Other communication channels such as wireless communication,wireline telephone, digital cable television, as well as otherpoint-to-point, point-to-multipoint, and broadcast communicationsmethods can also be used. The user interface or signal receiver 1188receives a signal from a remote signal source specifying information tobe utilized by system 1100. For example, the remote signal source canspecify the quantity of bioactive fluid to be dispensed or anauthorization code verifying the authority of the user to dispense thebioactive fluid. As shown in FIG. 11, the system 1100 can also becoupled to a provider system 1192 via network 1190.

[0098] The provider system 1192 includes a provider processor 1181,coupled to a provider display 1185, a provider storage device 1187, anda provider interface 1189. The provider interface 1189 is coupled viaprovider channel 1194 to the external communication network 1190. Theprovider system 1192 is utilized, for example, by a health care providersuch as a doctor, a pharmacist, a nurse, appropriate insurancepersonnel, or other appropriate health care professional. Although FIG.11 shows a single provider coupled to the system 1100 it also preferableto have multiple providers, such as doctors, pharmacists, nurses,insurance providers, and pharmaceutical manufacturers all coupled to thesystem 1100 over the external network 1190. This is particularlyadvantageous where system 1100 is located in a home where the patientcan request information on the bioactive fluid and appropriate dosageinformation from a pharmacist, request information on the ingestiblesheet from the manufacturer, and current health information from adoctor or nurse over the network; to form the appropriate pharmaceuticaldose for that time or multiple doses to cover a period of the next dayto several days or weeks. Such a system also allows potentially adversedrug interactions and individual allergies or intolerances andsensitivities to be flagged.

[0099] An exemplary embodiment of an interactive method for generating adosage form where the bioactive fluid is dispensed onto the ingestiblesheet is shown as flow diagrams in FIGS. 12-13. An overview of themethod is shown in FIG. 12. In step 1200, the various materials such asthe bioactive fluid and the ingestible sheet are loaded or inserted intoa bioactive fluid dispensing system. In Step 1210, informationindicative of the materials is read either by the system or by a userwho then manually enters the information into the system, such as thecomposition of the ingestible sheet and the active ingredients of thebioactive fluid. In step 1220, various forms of information arerequested by the system such as requesting from the doctor or pharmacistthe quantity or dose of the bioactive fluid to be dispensed. In step1230, various forms of information are specified and then transmittedand received by the system, such as the doctor or pharmacist specifyingthe quantity or dose of the bioactive fluid to be dispensed. Variousforms of information are verified in step 1240 such as verifying thatthe dose is within the correct range. The bioactive fluids as well asother materials such as the barrier material are dispensed on theingestible sheet in step 1250 providing all of verification steps weresuccessfully completed. In optional step 1260, appropriate user andmanufacturing information is printed on the ingestible sheet.

[0100] A more detailed view of the various steps associated with theloading step 1200 is shown in FIG. 13a. In step 1301, an off-axisbioactive fluid container is inserted into the dispensing system wherethe container, after insertion is fluidically coupled to a bioactivefluid reservoir of a semi-permanent cartridge. Either a replaceable orsemi-permanent bioactive fluid ejection cartridge is inserted in thedispensing system in step 1302. An off-axis ingestible ink container,and either a replaceable or semi-permanent ingestible ink ejectioncartridge, are inserted into the dispensing system in steps 1303 and1304 respectively, where the off-axis ink container is fluidicallycoupled to an ink reservoir in a semi-permanent ink cartridge. Dependingon the particular ingestible sheet, and bioactive fluid utilized, acartridge containing a mixture of the bioactive fluid and the ingestibleink can be inserted into the system in step 1305. In step 1306, aningestible sheet is loaded into the dispensing system.

[0101] A more detailed view of the various steps associated with thereading step 1210 is shown as a flow diagram in FIG. 13b. In step 1311,information is read from the ingestible sheet. For example, thecomposition or the expiration date of the ingestible sheet can be readby the system utilizing an image acquisition system scanning a bar code.Preferably this information is stored in a machine readable form,however, a human perceptible form can also be utilized. In steps 1312and 1314 information from the bioactive fluid cartridge and from thebioactive fluid container is accessed or read respectively. Preferablythis information is stored in a memory chip that this accessed, however,other means can also be utilized such as printing the information on thecartridge in a machine readable or human perceptible form.

[0102] A more detailed view of the various steps associated with therequesting step 1220 is shown as a flow diagram in FIG. 13c. In step1321 the quantity of the bioactive fluid to be dispensed is requested bythe bioactive fluid dispensing system. For example, this could bedisplayed on a display device located in the vicinity of the dispensingsystem or it can be displayed on a remote display device such a doctor'sor pharmacist's office. User information is requested by the system instep 1322. This information is any information about the user, i.e.typically the patient, that can be utilized for example in determiningthe appropriate dose, such as the patient's height, weight, age, etc. orinformation that is used by the user in administering the dosage form.In step 1324, manufacturer's information is requested by the system.This information is any information from the manufacturer of thebioactive fluid and/or the ingestible sheet. For example, thisinformation can be the same or similar to that obtained in steps 1311,1312, 1314 and can be used in conjunction with that information to actas a verification.

[0103] A more detailed view of the various steps associated with thespecifying step 1230 is shown as a flow diagram in FIG. 13d. In step1331, the quantity of the bioactive fluid to be dispensed is specified,for example by a doctor or pharmacist, transmitted to and received bythe bioactive fluid dispensing system. In step 1332, dosage information,such as dosage forms that vary the amount of bioactive fluid releasedover time as shown in FIG. 8, is specified, transmitted to and receivedby the system. User information is specified transmitted to and receivedby the system in step 1334. This information is any information aboutthe user, i.e. typically the patient, that can be utilized for examplein determining the appropriate dose, such as the patient's height,weight, age, etc. or information that is used by the user inadministering the dosage form. In step 1336, manufacturer's informationis specified. This information is any information from the manufacturerof the bioactive fluid and/or the ingestible sheet. For example, thisinformation can be the same or similar to that obtained in steps 1311,1312, 1314 and can be used in conjunction with that information to actas a verification.

[0104] A more detailed view of the various steps associated with theverifying step 1240 is shown as a flow diagram in FIG. 13e. In step1341, the dosage quantity is verified. Step 1341 verifies informationobtained in a previous step such as step 1331 or multiple steps is usedto verify the dosage specified, is either correct or within anacceptable range. For example, the information accessed from thebioactive fluid cartridge in step 1312 is compared to the specifiedquantity to be dispensed in step 1331. Another example would be the useof a third party authorization key where the dosage quantity is verifiedutilizing the key that is located on the user's system or is accessedvia a network such as the Internet. The dosage information specified instep 1332 is verified in step 1342. For example, if the information hasbeen previously entered then the information specified in step 1332 canbe verified from stored information stored on a storage device. However,if step 1332 is being performed for the first time with a given userthen either the information can be retransmitted back to the personspecifying or the information can be verified by a third party such as adoctor or an insurance agent via a network such as the Internet. In step1344, user information is verified. This step can also be carried outusing either previously stored information or a third party as describedabove in step 1342. The manufacturer's information is verified in step1346. This step can also be carried out using either previously storedinformation or a third party as described above in step 1342. Themanufacturer's information is any information from the manufacturer ofthe bioactive fluid or the ingestible sheet obtained in steps 1336 orstep 1210.

[0105] A more detailed view of the various steps associated with dosingof the bioactive fluid on the ingestible sheet in step 1250 is shown asa flow diagram in FIG. 13f provided the verification steps describedabove have been successfully completed. In step 1351, the quantity ofbioactive fluid to be dispensed is converted on a processor into anumber of activations of a fluid ejector. The ingestible sheet isadvanced into a fluid ejection area beneath the ejector head or heads instep 1352. The dosing data preferably in the form of the number ofactivations of a fluid ejector is transmitted from the processor to thedispense system in step 1354. In step 1356, the fluid ejectors areactivated to produce the pharmaceutical dose. Preferably, the drops areejected in a predetermined fluid swath pattern using dot matrixmanipulation, forming the pharmaceutical dose from the cartridgecontaining the bioactive fluid, however other processes of firing thefluid ejectors can also be utilized. In addition, a custom bioactivefluid dose can also be generated by inputting the user information, themanufacturing information, dosage information, as well as appropriateinformation from the bioactive fluid cartridge into a dose algorithm.The dose algorithm then combines this information in a predeterminedmanner to generate a custom bioactive fluid dose.

[0106] A more detailed view of the various steps associated withprinting information on the ingestible sheet, in step 1260, is shown asa flow diagram in FIG. 13g. In step 1361, appropriate manufacturinginformation, such as the composition of the ingestible sheet and thename or the bioactive composition, is printed on the ingestible sheet.The manufacturing information printed in step 1361 can be printed eitherin a machine understood form in step 1363 or it can be printed in ahuman perceptible form in step 1362 or in some combination thereof. Theuser information, such as the name of the user or patient and the dateand time for administering the dosage form, is printed on the ingestiblesheet in step 1364. In step 1366, preferably the barrier material isdispensed over the bioactive fluid previously dispensed in step 1356.However, depending on the particular ingestible sheet, bioactive fluid,and dosage structure (e.g. capsule or laminated structure) beingutilized, the barrier material may be dispensed before the bioactivefluid is dispensed.

[0107] The present invention can advantageously reduce the number oftherapeutically inactive materials, the number of dilutions, and thenumber of mixings in the manufacture of unit dosage forms. In addition,the bioactive fluid cartridge and the bioactive fluid dispensing systemof the present invention provides for the custom dispensing ofpharmaceutical unit dosage forms where the type of pharmaceutical andthe quantity of the selected drug can be easily varied to meet aspecific prescription. The bioactive fluid cartridge and the bioactivefluid dispensing system of the present invention provides the ability ofdispensing multiple, different pharmaceuticals in varied, selectedquantities to a single receiving medium thus simplifying the taking ofdrugs, especially combinations of different drugs by providing multipledrugs in one dose.

What is claimed is:
 1. A method of manufacturing a bioactive fluid doseon an ingestible sheet, comprising the steps of: advancing theingestible sheet to a dispense position; and activating a fluid ejectorto dispense at least one drop of a bioactive fluid onto the ingestiblesheet.
 2. The method of claim 1, further comprising the step of printingmanufacturing information onto the ingestible sheet.
 3. The method ofclaim 2, wherein said step of printing further comprises the step ofprinting said manufacturing information onto the ingestible sheet in amachine understood form.
 4. The method of claim 2, wherein said step ofprinting further comprises the step of printing said manufacturinginformation onto the ingestible sheet in a human-perceptible form. 5.The method of claim 2, wherein said step of printing further comprisesthe step of ejecting an ingestible ink from at least one ink ejectorfluidically coupled to an ink reservoir onto the ingestible sheet. 6.The method of claim 1, further comprising the step of sealing thedispensed bioactive fluid on the ingestible sheet.
 7. The method ofclaim 6, wherein the step of sealing further comprises the step ofactivating a second fluid ejector to eject a barrier component fluidover the dispensed bioactive fluid.
 8. The method of claim 1, whereinthe step of activating further comprises the step of activating saidfirst fluid ejector to eject a predetermined number of ejections of thebioactive fluid.
 9. The method of claim 1, wherein the step ofactivating further comprises the step of dispensing the bioactive fluidin a two dimensional array of bioactive fluid deposits onto theingestible sheet forming a dosage form.
 10. The method of claim 9,wherein the dosage form includes a first edge and a second edge, whereinthe density of the bioactive fluid deposits varies between the firstedge and the second edge, whereby a bioactive fluid gradient is formed.11. The method of claim 10, wherein the bioactive fluid gradient isadapted to provide a dosage form wherein after being ingested the amountof the bioactive fluid released increases over time.
 12. The method ofclaim 10, wherein the bioactive fluid gradient is adapted to provide adosage form wherein after being ingested the amount of the bioactivefluid released decreases over time.
 13. The method of claim 10, whereinthe bioactive fluid gradient is adapted to provide a dosage form whereinafter being ingested the amount of the bioactive fluid released remainsconstant over time.
 14. The method of claim 10, wherein the bioactivefluid gradient is adapted to provide a dosage form wherein after beingingested a discrete amount of the bioactive fluid is released in arepeatable manner over time.
 15. The method of claim 10, wherein thebioactive fluid gradient is adapted to provide a dosage form whereinafter being ingested a discrete amount of the bioactive fluid isreleased over different times.
 16. The method of claim 1, wherein thestep of activating further comprises the step of depositing essentiallya drop of a bioactive fluid onto the ingestible sheet wherein the fluidis in the range of from about ten femto-liter to about ten-micro-litervolume.
 17. A bioactive fluid dose on an ingestible sheet produced bythe method of claim
 1. 18. The method of claim 1, wherein the step ofactivating further comprises the step of dispensing the bioactive fluidin overlapping deposits forming essentially a layer of the bioactivefluid.
 19. The method of claim 1, wherein the step of activating furthercomprises the step of activating a second fluid ejector to dispense atleast a drop of a second bioactive fluid onto the ingestible sheet. 20.The method of claim 1, wherein the step of activating further comprisesthe step of activating a plurality of fluid ejectors to dispense atleast a drop of a plurality of bioactive fluids on a plurality ofingestible sheets wherein the plurality of bioactive fluids aredifferent.
 21. The method of claim 20, further comprising the step oflaminating the plurality of ingestible sheets.
 22. A bioactive fluiddose produced by the method of claim
 21. 23. The method of claim 1,wherein the step of activating further comprises the step of activatinga plurality of fluid ejectors to dispense at least a drop of a pluralityof bioactive fluids on the ingestible sheet, wherein the plurality ofbioactive fluids are different.
 24. A bioactive fluid dose produced bythe method of claim
 23. 25. A tablet using the method of claim 1, andfurther including a step of the step of encapsulating the ingestiblesheet thereby forming a tablet.
 26. The tablet of claim 25, wherein theingestible sheet is perforated.
 27. The method of claim 1, furthercomprising the step of printing user information on the ingestiblesheet.
 28. An interactive method of generating a custom bioactive fluiddose on an ingestible sheet, comprising the steps of: requesting aquantity of the bioactive fluid to be dispensed by a bioactive fluiddispensing system; receiving said quantity of the bioactive fluid doseto be dispensed by a bioactive fluid dispensing system, specified from afirst source; converting said quantity to a number of activations of afluid ejector on a processor; transmitting said number of activations toa drop-firing controller; advancing the ingestible sheet to a dispenseposition; and activating a first fluid ejector for said number ofactivations wherein each activation dispenses essentially a drop of abioactive fluid onto the ingestible sheet.
 29. The method of claim 28,further comprising the step of inserting a bioactive fluid containerinto the bioactive fluid dispensing system, wherein said bioactive fluidcontainer is fluidically coupled to a bioactive fluid reservoir of asemi-permanent cartridge.
 30. The method of claim 28, further comprisingthe step of inserting a replaceable bioactive fluid ejection cartridgeinto the bioactive fluid dispensing system.
 31. The method of claim 28,further comprising the step of inserting an ingestible ink containerinto the bioactive fluid dispensing system, wherein said ingestible inkcontainer is fluidically coupled to an ingestible ink reservoir of asemi-permanent ink cartridge.
 32. The method of claim 28, furthercomprising the step of inserting a replaceable ingestible ink ejectioncartridge into the bioactive fluid dispensing system.
 33. The method ofclaim 28, further comprising the step of reading information from theingestible sheet.
 34. The method of claim 33, wherein the information isstored in a machine readable form.
 35. The method of claim 33, whereinthe information is stored in a human perceptible form.
 36. The method ofclaim 28, further comprising the step of accessing information from thebioactive fluid cartridge.
 37. The method of claim 28, furthercomprising the step of accessing information from an off-axis bioactivefluid container.
 39. The method of claim 28, further comprising thesteps of: receiving dosage information specified from said first source;and verifying said dosage information from a second source.
 40. Themethod of claim 28, further comprising the steps of; requesting userinformation from said first source; receiving said user informationspecified by said first source; verifying said user information from asecond source; and printing said user information onto the ingestiblesheet provided said user information is verified.
 41. The method ofclaim 40, wherein said step of printing further comprises the step ofprinting a date and time for the custom bioactive fluid dose to beingested.
 42. The method of claim 40, wherein said step of printingfurther comprises the step of printing an image on the ingestible sheet.43. The method of claim 28, further comprising the steps of: requestingmanufacturing information from a second source; receiving saidmanufacturing information specified by said second source; verifyingsaid manufacturing information from a third source; and printing saidmanufacturing information onto the ingestible sheet provided saidmanufacturing information is verified.
 44. The method of claim 43,wherein said printing step further comprises the step of printing saidmanufacturing information onto the ingestible sheet in a machineunderstood form.
 45. The method of claim 43, wherein said printing stepfurther comprises the step of printing said manufacturing informationonto the ingestible sheet in a human-perceptible form.
 46. The method ofclaim 28 further comprising the step of verifying said quantity of thebioactive fluid to be dispensed.
 47. The method of claim 28, furthercomprising the steps of: receiving user information; receivingmanufacturing information; receiving dosage information; and accessing adose algorithm wherein said dose algorithm combines said user inputinformation and said manufacturing information with said dosageinformation in a predetermined manner to generate a custom bioactivefluid dose on the ingestible sheet.
 48. The method of claim 28, furthercomprising the step of ejecting a barrier component fluid over thebioactive fluid dispensed on the ingestible sheet.
 49. The method ofclaim 28, wherein the step of activating further comprises the step ofdispensing the bioactive fluid in a two dimensional array.
 50. Themethod of claim 28, wherein the step of activating further comprises thestep of depositing essentially a drop of a bioactive fluid onto theingestible sheet wherein the fluid is in the range of from about tenfemto-liter to about ten-micro-liter volume.
 51. A bioactive fluid doseon an ingestible sheet produced by the method of claim
 28. 52. Themethod of claim 28, further comprising the step of inserting a cartridgehaving a mixture of a bioactive active fluid and an ingestible ink in afluid reservoir.
 53. The method of claim 28, further comprising the stepof loading an ingestible sheet into the bioactive fluid dispensingsystem.
 54. A method of manufacturing a bioactive fluid dose on aningestible sheet comprising the steps of: inserting a fluid ejectioncartridge containing a mixture of an ingestible ink and a bioactivefluid in a reservoir forming a printable bioactive fluid; fluidicallycoupling said reservoir to at least one fluid ejector; advancing theingestible sheet to a dispense position; specifying a user message;printing said user message on the ingestible sheet using said printablebioactive fluid.
 55. An ingestible sheet usable in an apparatus formanufacturing a pharmaceutical dose comprising: a first dosage formhaving a first two dimensional array of deposits of a bioactive fluiddispensed thereon; and a second dosage form having a second twodimensional array of deposits of a bioactive fluid dispensed thereon;wherein said first dosage form and said second dosage from of theingestible sheet are not overlapping.
 56. An ingestible sheet usable inan apparatus for manufacturing a pharmaceutical dose comprising: a firstdosage form having a first two dimensional array of deposits of abioactive fluid dispensed thereon; and a second dosage form having asecond two dimensional array of deposits of a bioactive fluid dispensedthereon; wherein said first dosage form and said second dosage from ofthe ingestible sheet are overlapping
 57. The ingestible sheet of claim55, further comprising an information portion of the ingestible sheethaving manufacturing information disposed thereon.
 58. The ingestiblesheet of claim 57, wherein said manufacturing information includes atleast one item selected from the group consisting of, a date ofmanufacture, a composition of the ingestible sheet, an inspection date,an expiration date, quality control information, data on compatibilitywith bioactive fluids, and dispensing system parameters.
 59. Theingestible sheet of claim 57, wherein said information portion has userinformation disposed thereon.
 60. The ingestible sheet of claim 59,wherein said user information includes patient information.
 61. Theingestible sheet of claim 55, wherein said ingestible sheet furthercomprises a releasable backing.
 62. The ingestible sheet of claim 55,wherein said ingestible sheet contains a starch and glycerin-basedpaper.
 63. The ingestible sheet of claim 55, wherein said ingestiblesheet further comprises a pre-perforated sheet.
 64. The ingestible sheetof claim 55, wherein said ingestible sheet further comprises a componentselected from the group consisting of starch, glycerin, gelatin,cellulose, polysaccharides, and any combination thereof.
 65. Theingestible sheet of claim 55, wherein said ingestible sheet furthercomprises a component selected from the group consisting of restructuredfruits, restructured vegetables, and any combination thereof.
 66. Theingestible sheet of claim 55, wherein said ingestible sheet contains awater expandable foam.
 67. The ingestible sheet of claim 55, whereinsaid ingestible sheet has a thickness from about 10 to about 350microns.
 68. A kit for producing a pharmaceutical dose comprising: atleast one ingestible sheet; and a fluid ejection cartridge containing atleast one bioactive fluid in a reservoir, wherein said at least onebioactive fluid is compatible with said at least one ingestible sheet.69. The kit of claim h1, wherein said fluid ejection cartridge furthercomprises an ingestible ink contained in a second reservoir.
 70. The kitof claim h1, wherein said fluid ejection cartridge further comprises abarrier material contained in a second reservoir.
 71. The kit of claimh1, further comprises a second fluid ejection cartridge containing atleast one ingestible ink.
 72. The kit of claim h1, further comprises asecond fluid ejection cartridge containing at least one barriermaterial.